Staphylococcus aureus has historically been a leading cause of nosocomial infections in humans worldwide. In the past several decades the emergence of methicillin-resistant S. aureus (MRSA) harboring multiple antibiotic resistance determinants has left relatively few therapeutic options available. Today, these strains have made their way into the community and now pose a very serious public health threat, causing more deaths per year than HIV-AIDS. The University of Nebraska Medical Center has committed to advancing research into the staphylococci with the hiring of several new researchers, and the concerted collaboration with regional investigators, who are all focused on this important pathogen. These researchers have expertise in varied aspects of the staphylococci including: biofilm development, gene regulation, physiology, and the immunology of staphylococcal infections. The hypothesis to be tested by this team in this application is that S. aureus biofilm formation involves complex developmental processes that affect the host immune response. The application includes four projects centered around staphylococcal biofilm and disease including: regulated cell death during biofilm development (Project 1, K. Bayles); effect of arginine metabolism on biofilm formation in the staphylococci (Project 2, P. Fey); the role of nuclease in biofilm development and disease (Project 3, A. Horswill); and innate immunity to S. aureus biofilm (Project 4, T. Kielian). The cores include: Biofilm Growth and Analysis Core (Core A, J. Bose); Bioimaging Core (Core B, T. Fritz); and Administrative Core (Core C, K. Bayles). Each project involves highly collaborative and synergistic research endeavors and relies heavily on the cores. These efforts will have a dramatic impact on our understanding of biofilm formation in the staphylococci and the effect it has on the host response. Ultimately, these studies will pave the way for novel therapeutic approaches for the treatment of staphylococcal infections.